March 30, 2017
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Clozaril

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Clozaril




Indications
Dosage
How Supplied

INDICATIONS

Treatment-Resistant Schizophrenia

CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see WARNINGS AND PRECAUTIONS].

The effectiveness of CLOZARIL in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing CLOZARIL and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies].

Reduction In The Risk Of Recurrent Suicidal Behavior In Schizophrenia Or Schizoaffective Disorder

CLOZARIL is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies].

DOSAGE AND ADMINISTRATION

Required Laboratory Testing Prior To Initiation And During Therapy

Prior to initiating treatment with CLOZARIL, a baseline ANC must be obtained. The baseline ANC must be at least 1500/μL for the general population, and at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see WARNINGS AND PRECAUTIONS].

Dosing Information

The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see WARNINGS AND PRECAUTIONS].

CLOZARIL can be taken with or without food [see Pharmacokinetics].

Maintenance Treatment

Generally, patients responding to CLOZARIL should continue maintenance treatment on their effective dose beyond the acute episode.

Discontinuation Of Treatment

Method of treatment discontinuation will vary depending on the patient's last ANC:

  • See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia.
  • Reduce the dose gradually over a period of 1 to 2 weeks if termination of CLOZARIL therapy is planned and there is no evidence of moderate to severe neutropenia.
  • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≤ 1500/μL and for BEN patients until their ANC is ≤ 1000/μL or above their baseline.
  • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see WARNINGS AND PRECAUTIONS].
  • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Re-Initiation Of Treatment

When restarting CLOZARIL in patients who have discontinued CLOZARIL (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see WARNINGS AND PRECAUTIONS] If that dose is well-tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

Dosage Adjustments With Concomitant Use Of CYP1A2, CYP2D6, CYP3A4 Inhibitors Or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John's wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [See DRUG INTERACTIONS].

Table 1: Dose Adjustment in Patients Taking Concomitant Medications

Co-medications Scenarios
Initiating CLOZARIL while taking a co-medication Adding a co-medication while taking CLOZARIL Discontinuing a co-medication while continuing CLOZARIL
Strong CYP1A2 Inhibitors Use one third of the CLOZARIL dose. Increase CLOZARIL dose based on clinical response.
Moderate or Weak CYP1A2 Inhibitors Monitor for adverse reactions. Consider reducing the CLOZARIL dose if necessary. Monitor for lack of effectiveness. Consider increasing CLOZARIL dose if necessary.
CYP2D6 or CYP3A4 Inhibitors
Strong CYP3A4 Inducers Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the CLOZARIL dose. Monitor for decreased effectiveness. Reduce CLOZARIL dose based on clinical response.
Moderate or weak CYP1A2 or CYP3A4 Inducers Monitor for decreased effectiveness. Consider increasing the CLOZARIL dose if necessary. Monitor for adverse reactions. Consider reducing the CLOZARIL dose if necessary.

Renal Or Hepatic Impairment Or CYP2D6 Poor Metabolizers

It may be necessary to reduce the CLOZARIL dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations].

HOW SUPPLIED

Dosage Forms And Strengths

CLOZARIL (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

Storage And Handling

CLOZARIL® (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

CLOZARIL® (clozapine) Tablets
25 mg

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “25” once on the other side.

Bottle of 100...........................NDC 0078-0126-05
Bottle of 500...........................NDC 0078-0126-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip............................ NDC 0078-0126-06

100 mg

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “100” once on the other side.

Bottle of 100...........................NDC 0078-0127-05
Bottle of 500...........................NDC 0078-0127-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip............................ NDC 0078-0127-06

Storage And Handling

Storage temperature should not exceed 30°C (86°F).

Keep out of reach of children.

Revised: Sep 2015

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/17/2016

Indications
Dosage
How Supplied

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